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ZEBRAFISH MODELS FOR DRAVET SYNDROME RESEARCH AND DISCOVERY

用于 Dravet 综合征研究和发现的斑马鱼模型

基本信息

批准号：
9912373
负责人：
Scott C Baraban
金额：
$ 48.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9912373
关键词：
Agonist Award Behavior Behavioral Benchmarking Biological Biological Assay Blinded Brain CRISPR/Cas technology Calcium Cells Child Clinical Colorado Communities Development Disease Drug resistance Electrodes Electrophysiology (science)Elements Epilepsy Etiology Exhibits Failure Family Functional disorder Gene Mutation Generations Genetic Goals Human Image Imaging Techniques Impairment Investigation Larva Libraries Locomotion Metabolic dysfunction Microfluidics Modeling Mutation National Institute of Neurological Disorders and Stroke Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Phenotype Research Resistance Resolution Seizures Serotonin Signal Pathway Social Development Sodium Channel Techniques Technology Time Transgenic Organisms Work Zebrafish analog analysis pipeline base blind calcium indicator childhood epilepsy comorbidity confocal imaging de novo mutation design dravet syndrome drug candidate drug development drug discovery drug use screening effective therapy excitatory neuron genome editing high risk high-throughput drug screening improved in vivo inhibitory neuron insight kinase inhibitor loss of function multidisciplinary mutant neural network novel preclinical development preclinical study receptor research and development screening severe intellectual disability side effect sudden unexpected death in epilepsy tool voltage

项目摘要

Project Summary/Abstract Dravet syndrome (DS), a catastrophic childhood epilepsy, is associated with severe intellectual disability, impaired social development, persistent drug-resistant seizures and a high risk of sudden unexpected death in epilepsy. Our recent investigation of zebrafish mutants featuring a loss-of-function sodium channel (scn1a) mutation (e.g., a gene mutation identified in ~80% of DS patients) focused on drug discovery and development, metabolic dysfunction and behavioral comorbidities. Using a high-throughput phenotype-based screening strategy and medicinal chemistry, we screened nearly 3000 drugs, successfully identified a serotonin (5HT) receptor mechanism underlying anti-seizure activity of clemizole and developed three novel clemizole analogs. Using CRISPR/Cas9 genome editing technology we generated new zebrafish mutant lines for chd2, gabrb3, pcdh19 and stxbp1 (e.g., de novo mutations seen in ~20% of DS patients). Interestingly, stxbp1 and gabrb3 mutants exhibit epileptic phenotypes. We also designed and manufactured a microfluidic, multi-channel electrode-integrated platform for long-term non-invasive electrophysiology on larval zebrafish (Hong et al. 2016) and developed a calcium imaging-analysis pipeline for studying seizure macro- and micro- networks in vivo (Liu and Baraban 2019). The proposed work will leverage these unique tools. Three specific aims are proposed: (i) to resolve neural networks responsible for seizures in larval DS zebrafish, (ii) to perform high-throughput drug screening using zebrafish and (iii) to further evaluate clemizole and related anti-seizure compounds. Techniques will include automated locomotion tracking, in vivo zebrafish electrophysiology, pharmacology, and fast calcium imaging using genetically encoded calcium- and voltage-sensitive indicators. Our results promise to simultaneously advance our long-term goals (i) to better understand the pathophysiology of genetic epilepsies and (ii) identify promising new treatment options for these intractable conditions.

项目总结/文摘